@article{29b921f3efe14f7e9cf03bf7bdba8bfa,
title = "ATR inhibition potentiates ionizing radiation-induced interferon response via cytosolic nucleic acid-sensing pathways",
abstract = "Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module should help to maximize the efficacy of radiotherapy. In the current study, we report that inhibitors of the DNA damage response kinase ATR can significantly potentiate ionizing radiation-induced innate immune responses. Using a series of mammalian knockout cell lines, we demonstrate that, surprisingly, both the cGAS/STING-dependent DNA-sensing pathway and the MAVS-dependent RNA-sensing pathway are responsible for type I interferon signaling induced by ionizing radiation in the presence or absence of ATR inhibitors. The relative contributions of these two pathways in type I interferon signaling depend on cell type and/or genetic background. We propose that DNA damage-elicited double-strand DNA breaks releases DNA fragments, which may either activate the cGAS/STING-dependent pathway or—especially in the case of AT-rich DNA sequences—be transcribed and initiate MAVS-dependent RNA sensing and signaling. Together, our results suggest the involvement of two distinct pathways in type I interferon signaling upon DNA damage. Moreover, radiation plus ATR inhibition may be a promising new combination therapy against cancer.",
keywords = "ATR, MAVS, cGAS/STING, radiation, type I interferon",
author = "Xu Feng and Anthony Tubbs and Chunchao Zhang and Mengfan Tang and Sriram Sridharan and Chao Wang and Dadi Jiang and Dan Su and Huimin Zhang and Zhen Chen and Litong Nie and Yun Xiong and Min Huang and Andr{\'e} Nussenzweig and Junjie Chen",
note = "Funding Information: We thank all members of the Chen laboratory for their help and constructive discussion. We thank MD Anderson's Flow Cytometry and Cellular Imaging Facility and Science Park NGS Facility for their help with the flow cytometry and RNA-seq experiments, respectively (supported by MD Anderson's NIH Cancer Center Support Grant, P30CA016672). We thank Dr. Pawel Mazur, Li Ma and Dr. Steven H. Lin (MD Anderson Cancer Center) for providing cell lines. We thank Dr. Yi Li and Amy Tsu Ku (Baylor College of Medicine) for their help on isolating mouse primary mammary epithelial cells. This work was supported in part by institutional funds and the Pamela and Wayne Garrison Distinguished Chair in Cancer Research. J.C. also received support from CPRIT (RP160667) and NIH (CA157448, CA193124, CA210929, CA216911, and CA216437). Funding Information: We thank all members of the Chen laboratory for their help and constructive discussion. We thank MD Anderson's Flow Cytometry and Cellular Imaging Facility and Science Park NGS Facility for their help with the flow cytometry and RNA‐seq experiments, respectively (supported by MD Anderson's NIH Cancer Center Support Grant, P30CA016672). We thank Dr. Pawel Mazur, Li Ma and Dr. Steven H. Lin (MD Anderson Cancer Center) for providing cell lines. We thank Dr. Yi Li and Amy Tsu Ku (Baylor College of Medicine) for their help on isolating mouse primary mammary epithelial cells. This work was supported in part by institutional funds and the Pamela and Wayne Garrison Distinguished Chair in Cancer Research. J.C. also received support from CPRIT (RP160667) and NIH (CA157448, CA193124, CA210929, CA216911, and CA216437). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = jul,
day = "15",
doi = "10.15252/embj.2019104036",
language = "English (US)",
volume = "39",
journal = "EMBO Journal",
issn = "0261-4189",
publisher = "Nature Publishing Group",
number = "14",
}